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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.

ABSTRACT: Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.

SUBMITTER: Went M

PROVIDER: S-EPMC6137048 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.

Went Molly M Sud Amit A Försti Asta A Halvarsson Britt-Marie BM Weinhold Niels N Kimber Scott S van Duin Mark M Thorleifsson Gudmar G Holroyd Amy A Johnson David C DC Johnson David C DC Li Ni N Orlando Giulia G Law Philip J PJ Ali Mina M Chen Bowang B Mitchell Jonathan S JS Gudbjartsson Daniel F DF Kuiper Rowan R Stephens Owen W OW Bertsch Uta U Broderick Peter P Campo Chiara C Bandapalli Obul R OR Einsele Hermann H Gregory Walter A WA Gullberg Urban U Hillengass Jens J Hoffmann Per P Jackson Graham H GH Jöckel Karl-Heinz KH Johnsson Ellinor E Kristinsson Sigurður Y SY Mellqvist Ulf-Henrik UH Nahi Hareth H Easton Douglas D Pharoah Paul P Dunning Alison A Peto Julian J Canzian Federico F Swerdlow Anthony A Eeles Rosalind A RA Kote-Jarai ZSofia Z Muir Kenneth K Pashayan Nora N Nickel Jolanta J Nöthen Markus M MM Rafnar Thorunn T Ross Fiona M FM da Silva Filho Miguel Inacio MI Thomsen Hauke H Turesson Ingemar I Vangsted Annette A Andersen Niels Frost NF Waage Anders A Walker Brian A BA Wihlborg Anna-Karin AK Broyl Annemiek A Davies Faith E FE Thorsteinsdottir Unnur U Langer Christian C Hansson Markus M Goldschmidt Hartmut H Kaiser Martin M Sonneveld Pieter P Stefansson Kari K Morgan Gareth J GJ Hemminki Kari K Nilsson Björn B Houlston Richard S RS

Nature communications 20180913 1

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ ...[more]

PMID: 30213928

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Project description:Background & aimsKnown genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC.MethodsThis discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases.ResultsWe identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2.ConclusionsWe identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

Dataset Information

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.

Publications

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.

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